Type 1 diabetes results from the destruction of the insulin-secreting -cells by an immune mediated process. The increasing incidence of type 1 diabetes around the world, especially among children, has been of great concern. Despite intensive efforts to identify the underlying causes of this disease, it is still not clear why -cels are destroyed, what triggers the initial immune destruction and how it could be prevented or reversed. Endoplasmic reticulum (ER) stress, caused by protein misfolding, chronic inflammation and environmental factors, is emerging as a novel paradigm for diabetes pathogenesis. To cope with ER stress, the Unfolded Protein Response (UPR), a signaling cascade mediated by ER membrane-localized sensors ATF6, IRE1 and PERK, is triggered to re-establish cellular homeostasis. ER stress and aberrant UPR have been shown to play a role in the pathogenesis of inflammatory and autoimmune diseases including type 2 diabetes and atherosclerosis. However, the role of ER stress and the UPR in pathophysiology and in the initiation and propagation of the autoimmune responses in T1DM remains incompletely defined. We claim that the loss of ER adaptive capacity in -cells early in disease progression can lead not only to b-cell dysfunction, but also contribute to an aggravated autoimmune response. For this three- year Mentored Research Scientist Development K-Award training period, and with the guidance of my K01 mentorship team, I propose the following training and research plan: 1) a strategic four-pronged training approach to learn how to design, lead and execute a multidisciplinary research project, and 2) as the research objective of this application, collect preliminary data for a future RO1 grant. The research application has two specific aims: Aim 1: To determine the role of ATF6 in -cells during different stages of disease progression. We hypothesize that losing the ATF6 branch of the UPR during diabetes progression will disrupt b-cell function, and depending on the stage of the deletion, it will also affect insulitis developmen. To test this hypothesis, we will use a recently generated mouse model that allows us to inducibly delete ATF6 specifically in -cells at defined times during disease progression in non-obese diabetic (NOD) mice. Aim 2: To examine cell non-autonomous effects of -cell ER stress on lymphocyte proliferation, activation, migration and polarization. We hypothesize that -cell stress can be sensed by lymphocytes and that this extrinsic stress can lead to phenotypic and/or molecular changes in immune cells. We will test this hypothesis by using ex vivo co-culture systems and in vivo adoptive transfer experiments. The expected outcome of the proposed work is a detailed characterization of the ATF6 branch of the UPR and new understanding of a previously unstudied area of ER stress-driven cross talk between -cells and immune cells. This work has the potential to make an important impact on understanding the role of ER stress in T1DM and promote development of better therapeutic and preventive strategies.